VIOLET: A phase I/II trial evaluation of radioligand treatment in men with metastatic castration-resistant prostate cancer with [<sup>161</sup>Tb]Tb-PSMA-I&amp;T.
Authors: James Patrick Buteau, Louise Kathleen Kostos, Ramin Alipour, Price Jackson, Lachlan McIntosh, Brittany Emmerson, Mohammad B Haskali, Theresa Yeung, Sophia Xie, Elizabeth Medhurst, Rajeev Ravi, Brian D. Gonzalez, Heidi Fettke, Nicole Ng, Maria Docanto, Patricia Bukczynska, Benjamin Blyth, Luc Furic, Arun Azad, Michael S Hofman
Journal: Journal of Clinical Oncology (2023)

TPS281 Background: [ 177 Lu]Lu-PSMA is an effective class of therapy for men with metastatic castration-resistant prostate cancer (mCRPC); however, progression is inevitable. The limited durability of response is partially explained by the presence of micrometastatic deposits. Single tumor cells and micrometastases are energy-sheltered deposits receiving low absorbed radiation, due to the ~0.7mm mean path-length of Lutetium-177 ( 177 Lu). Terbium-161 ( 161 Tb) has abundant emission of Auger electrons that deposit a higher concentration of radiation over a shorter path, particularly to single tumor cells and micrometastases. 161 Tb has shown superior in-vitro and in-vivo results in comparison with 177 Lu. We hypothesize that [ 161 Tb]Tb-PSMA-I&amp;T will deliver effective radiation to sites of metastatic prostate cancer with an acceptable safety profile. Methods: This single-center, single-arm, phase I/II trial will recruit 30 to 36 men with progressive mCRPC. The phase I dose-escalation is designed with a 3+3 model to establish the safest dose of [ 161 Tb]Tb-PSMA-I&amp;T (dose levels: 4.4, 5.5 and 7.4 GBq). The maximum tolerated dose (MTD) will be defined as the highest dose level at which a dose-limiting toxicity occurs in less than 1/3 or 2/6 participants. The phase II dose-expansion will include 24 participants at the MTD. Up to six cycles of [ 161 Tb]Tb-PSMA-I&amp;T will be administered intravenously every six weeks, with each subsequent dose for each patient reduced by 0.4GBq. Key eligibility criteria include a diagnosis of mCRPC with progression after at least one line of taxane chemotherapy and a second-generation anti-androgen, PSMA-positive disease on PSMA PET/CT (SUVmax ≥20), no sites of discordance on FDG PET/CT, adequate bone marrow, hepatic and renal function, ECOG performance status ≤2, and no prior treatment with another radioisotope. The co-primary objectives are to establish the MTD of [ 161 Tb]Tb-PSMA-I&amp;T, and safety profile [CTCAE v5.0]. Secondary objectives include measuring absorbed radiation dose [Gray], evaluating anti-tumour activity [PSA 50% response rate, radiographic and PSA progression-free survival, overall survival, objective response rate], and evaluation of pain [BPI-SF] and health-related quality of life [FACT-P and FACT-RNT] over the first 12 months after treatment commences. Exploratory objectives include ctDNA analysis at baseline, during treatment and at progression, and optional tissue biopsies, to determine biomarkers of treatment response and resistance. Patient enrolment began in October 2022, with recruitment expected to continue for 24 months. Clinical trial information: NCT05521412 .